- Email: [email protected]
deletion polymorphism with schizophrenia: A meta-analysis
Psychiatry Research 220 (2014) 1169–1171
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Association of the angiotensin-converting enzyme gene insertion/deletion polymorphism with schizophrenia: A meta-analysis
1. Introduction Angiotensin-converting enzyme (ACE) is a key enzyme which catalyzes the conversion of angiotensin I to angiotensin II and modulates the dopamine (DA) turnover in the midbrain. An insertion/deletion (I/D) polymorphism resulting from the presence or absence of a 287 bp fragment in intron 16 of the ACE gene is associated with ACE levels (Rigat et al., 1990). Recent studies have been carried out in different ethnic populations. Eight studies (Arinami et al., 1996; Ouyang et al., 2001; Segman et al., 2002; Illi et al., 2003; Meerabux et al., 2005; Baskan et al., 2010; Nadalin et al., 2012; Hui et al., 2014) showed negative associations and two studies (Crescenti et al., 2009; Kucukali et al., 2010;) showed positive associations between the ACE I/D polymorphism and SCZ. We believe that these controversial results may be mainly caused by the relatively small sample size. To further evaluate these conflicting findings and to derive a more precise estimation about whether the ACE I/D polymorphism confers an increased risk of development of SCZ, we conducted the meta-analysis based on the previous reports using the RevMan (v.5.1) program. The research may provide a useful support for the genetic etiology of SCZ. Four online electronic databases (PubMed, CNKI, VIP and WanFang) were searched (the last search update was March 2014) using the following keywords and subject terms: “angiotensin-converting enzyme” or “ACE” AND “schizophrenia”. We selected only published articles written in English or Chinese. Studies included in the current meta-analysis had to meet the following criteria: (1) case-control study design; (2) the study must focus on ACE I/D polymorphism using original data and be published in a peer-reviewed journal; (3) the study must provide sufficient data to calculate the odds ratio (OR), confidence interval (CI) and P value; (4) the study must specify the genotyping methods or provide appropriate reference; (5) genotype distribution of all control groups must be in Hardy–Weinberg equilibrium (HWE); (6) all clinical diagnoses of schizophrenia or schizoaffective disorder patients must fulfill the criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM). Finally, ten casecontrol studies involving 1905 patients and 2351 healthy controls
http://dx.doi.org/10.1016/j.psychres.2014.08.027 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
were included in the current meta-analysis. The strength of the association between ACE I/D polymorphism and SCZ was measured by odds ratios (ORs) with 95% confidence intervals (CIs). We evaluated the association between ACE I/D polymorphism and SCZ using a fixed-effects or random-effects model via heterogeneity analysis. The statistical results indicated that ACE I/D polymorphism was not associated with susceptibility to SCZ (Fig. 1). Moreover, ethnic-dependent subgroup analysis was also performed according to ethnicity. However, we did not observe any positive association (data not shown). The power of the present metaanalysis is about 80%. In addition, the removal of any study one by one did not alter the statistical results and no significant publication bias was observed (data not shown). Compared to the previous study, the present meta-analysis including increased sample size and study data from different races provided some new insights into the relationship between ACE I/D polymorphism and SCZ and obtained conclusive results to some extent. In interpreting the results of the meta-analysis, some limitations should be addressed. First, SCZ is a multifactorial disease affected by both inherited and environmental factors. The potential gene-gene or/and gene-environment interactions may also modify the development of SCZ. Absence of these factors might influence the effect of ACE I/D polymorphism in susceptibility to SCZ in the present study. Second, although the significant association between the Positive and Negative Syndrome Scale (PANSS) and ACE I/D polymorphism had been observed in previous studies (Nadalin et al., 2012; Hui et al., 2014), we did not perform a stratified association analysis between ACE I/D polymorphism and clinical phenotypes because most of previous studies did not provide adequate information of clinical measures results. Third, age at onset (AAO)-specific and/or sex-specific risk loci have been identified in the previous studies (Kantojarvi et al., 2010; Wang et al., 2011; Yuan et al., 2013). However, due to the absence of detailed information, we did not perform a stratified analysis by AAO or gender either. Fourth, different genotyping methods may have a possible effect on the frequency of the allele, and the genetic heterogeneity of the ACE I/D polymorphism may exist in diverse ethnic populations. Taken together, despite some limitations, we provide important evidence to support the findings that ACE I/D polymorphism may be not associated with susceptibility to SCZ. However, we could not completely exclude the possibility that other SNPs within the ACE gene modify development of SCZ. Future researches with larger cohorts should be warranted.
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Letter to the Editor / Psychiatry Research 220 (2014) 1169–1171
Fig. 1. Forest plot for the association between ACE I/D polymorphism and SCZ risk. Each study is shown according to the point estimate of OR with 95% CI. A: Allelic model (D vs. I); B: Homozygotes model (DD vs. II); C: Dominant model (DDþ ID vs. II); D: Recessive model (DD vs. IDþ II).
Letter to the Editor / Psychiatry Research 220 (2014) 1169–1171
Acknowledgments This work was supported by the National Natural Science Foundation of China (No.81301147). References Arinami, T., Li, L., Mitsushio, H., Itokawa, M., Hamaguchi, H., Toru, M., 1996. An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and affective disorders. Biological Psychiatry 40, 1122–1127. Baskan, N.M., Basaran, A., Yenilmez, C., Kurt, H., Ozdemir, F., Gunes, H.V., Degirmenci, I., 2010. Investigation of association between Angiotensin-converting enzyme gene insertion/deletion polymorphism frequency in Turkish patients with schizophrenia. Genetic Testing and Molecular Biomarkers 14, 753–757. Crescenti, A., Gasso, P., Mas, S., Abellana, R., Deulofeu, R., Parellada, E., Bernardo, M., Lafuente, A., 2009. Insertion/deletion polymorphism of the angiotensinconverting enzyme gene is associated with schizophrenia in a Spanish population. Psychiatry Research e165, 175–180. Hui, L., Wu, J.Q., Zhang, X., Lv, J., Du, W.L., Kou, C.G., Yu, Y.Q., Lv, M.H., Chen da, C., Zhang, X.Y., 2014. Association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and first-episode patients with schizophrenia in a Chinese Han population. Human Psychopharmacology 29, 274–279. Illi, A., Kampman, O., Anttila, S., Roivas, M., Mattila, K.M., Lehtimaki, T., Leinonen, E., 2003. Interaction between angiotensin-converting enzyme and catechol-Omethyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. European Neuropsychopharmacology 13, 147–151. Kantojarvi, K., Onkamo, P., Vanhala, R., Alen, R., Hedman, M., Sajantila, A., Nieminen-von Wendt, T., Jarvela, I., 2010. Analysis of 9p24 and 11p12-13 regions in autism spectrum disorders: rs1340513 in the JMJD2C gene is associated with ASDs in Finnish sample. Psychiatric Genetics 20, 102–108. Kucukali, C.I., Aydin, M., Ozkok, E., Bilge, E., Zengin, A., Cakir, U., Kara, I., 2010. Angiotensin-converting enzyme polymorphism in schizophrenia, bipolar disorders, and their first-degree relatives. Psychiatric Genetics 20, 14–19. Meerabux, J., Iwayama, Y., Sakurai, T., Ohba, H., Toyota, T., Yamada, K., Nagata, R., Irukayama-Tomobe, Y., Shimizu, H., Yoshitsugu, K., Ohta, K., Yoshikawa, T., 2005. Association of an orexin 1 receptor 408Val variant with polydipsiahyponatremia in schizophrenic subjects. Biological Psychiatry 58, 401–407. Nadalin, S., Buretic-Tomljanovic, A., Rubesa, G., Jonovska, S., Tomljanovic, D., Ristic, S., 2012. Angiotensin-converting enzyme gene insertion/deletion polymorphism is not associated with schizophrenia in a Croatian population. Psychiatric Genetics 22, 267–268. Ouyang, W.C., Wang, Y.C., Hong, C.J., Cheng, C.Y., Tsai, S.J., 2001. Association study of angiotensin-converting enzyme gene polymorphism with schizophrenia and polydipsia. Neuropsychobiology 44, 31–35.
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Rigat, B., Hubert, C., Alhenc-Gelas, F., Cambien, F., Corvol, P., Soubrier, F., 1990. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. Journal of Clinical Investigation 86, 1343–1346. Segman, R.H., Shapira, Y., Modai, I., Hamdan, A., Zislin, J., Heresco-Levy, U., Kanyas, K., Hirschmann, S., Karni, O., Finkel, B., Schlafman, M., Lerner, A., Shapira, B., Macciardi, F., Lerer, B., 2002. Angiotensin converting enzyme gene insertion/ deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia. American Journal of Medical Genetics 114, 310–314. Wang, K.S., Liu, X., Zhang, Q., Aragam, N., Pan, Y., 2011. Genome-wide association analysis of age at onset in schizophrenia in a European-American sample. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 156B, 671–680. Yuan, J., Jin, C., Qin, H.D., Wang, J., Sha, W., Wang, M., Zhang, Y., Zhang, F., Li, J., Yu, S., Qi, S., Shugart, Y.Y., 2013. Replication study confirms link between TSPAN18 mutation and schizophrenia in Han Chinese. PLoS One 8, e58785.
Guofu Zhang Wuxi Mental Health Center Affiliated to Nanjing Medical University, Wuxi 214151, Jiangsu Province, China Mental Health Institute of The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China Feng Zhang, Jianzhong Zhu, Fuquan Zhang, Jianmin Yuan, Chunhui Jin n Wuxi Mental Health Center Affiliated to Nanjing Medical University, Wuxi 214151, Jiangsu Province, China E-mail address: [email protected] (C. Jin) Zhimin Xue nn Mental Health Institute of The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China E-mail address: [email protected] 16 August 2014 Available online 16 September 2014
n nn
Corresponding author. Tel.: þ 86 510 83250132; fax: þ 86 510 83012201. Corresponding author. Tel.: þ 86 731 85294015; fax: þ86 731 85533525.
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Association of the angiotensin-converting enzyme gene insertion/deletion polymorphism with schizophrenia: A meta-analysis
1. Introduction Angiotensin-converting enzyme (ACE) is a key enzyme which catalyzes the conversion of angiotensin I to angiotensin II and modulates the dopamine (DA) turnover in the midbrain. An insertion/deletion (I/D) polymorphism resulting from the presence or absence of a 287 bp fragment in intron 16 of the ACE gene is associated with ACE levels (Rigat et al., 1990). Recent studies have been carried out in different ethnic populations. Eight studies (Arinami et al., 1996; Ouyang et al., 2001; Segman et al., 2002; Illi et al., 2003; Meerabux et al., 2005; Baskan et al., 2010; Nadalin et al., 2012; Hui et al., 2014) showed negative associations and two studies (Crescenti et al., 2009; Kucukali et al., 2010;) showed positive associations between the ACE I/D polymorphism and SCZ. We believe that these controversial results may be mainly caused by the relatively small sample size. To further evaluate these conflicting findings and to derive a more precise estimation about whether the ACE I/D polymorphism confers an increased risk of development of SCZ, we conducted the meta-analysis based on the previous reports using the RevMan (v.5.1) program. The research may provide a useful support for the genetic etiology of SCZ. Four online electronic databases (PubMed, CNKI, VIP and WanFang) were searched (the last search update was March 2014) using the following keywords and subject terms: “angiotensin-converting enzyme” or “ACE” AND “schizophrenia”. We selected only published articles written in English or Chinese. Studies included in the current meta-analysis had to meet the following criteria: (1) case-control study design; (2) the study must focus on ACE I/D polymorphism using original data and be published in a peer-reviewed journal; (3) the study must provide sufficient data to calculate the odds ratio (OR), confidence interval (CI) and P value; (4) the study must specify the genotyping methods or provide appropriate reference; (5) genotype distribution of all control groups must be in Hardy–Weinberg equilibrium (HWE); (6) all clinical diagnoses of schizophrenia or schizoaffective disorder patients must fulfill the criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM). Finally, ten casecontrol studies involving 1905 patients and 2351 healthy controls
http://dx.doi.org/10.1016/j.psychres.2014.08.027 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
were included in the current meta-analysis. The strength of the association between ACE I/D polymorphism and SCZ was measured by odds ratios (ORs) with 95% confidence intervals (CIs). We evaluated the association between ACE I/D polymorphism and SCZ using a fixed-effects or random-effects model via heterogeneity analysis. The statistical results indicated that ACE I/D polymorphism was not associated with susceptibility to SCZ (Fig. 1). Moreover, ethnic-dependent subgroup analysis was also performed according to ethnicity. However, we did not observe any positive association (data not shown). The power of the present metaanalysis is about 80%. In addition, the removal of any study one by one did not alter the statistical results and no significant publication bias was observed (data not shown). Compared to the previous study, the present meta-analysis including increased sample size and study data from different races provided some new insights into the relationship between ACE I/D polymorphism and SCZ and obtained conclusive results to some extent. In interpreting the results of the meta-analysis, some limitations should be addressed. First, SCZ is a multifactorial disease affected by both inherited and environmental factors. The potential gene-gene or/and gene-environment interactions may also modify the development of SCZ. Absence of these factors might influence the effect of ACE I/D polymorphism in susceptibility to SCZ in the present study. Second, although the significant association between the Positive and Negative Syndrome Scale (PANSS) and ACE I/D polymorphism had been observed in previous studies (Nadalin et al., 2012; Hui et al., 2014), we did not perform a stratified association analysis between ACE I/D polymorphism and clinical phenotypes because most of previous studies did not provide adequate information of clinical measures results. Third, age at onset (AAO)-specific and/or sex-specific risk loci have been identified in the previous studies (Kantojarvi et al., 2010; Wang et al., 2011; Yuan et al., 2013). However, due to the absence of detailed information, we did not perform a stratified analysis by AAO or gender either. Fourth, different genotyping methods may have a possible effect on the frequency of the allele, and the genetic heterogeneity of the ACE I/D polymorphism may exist in diverse ethnic populations. Taken together, despite some limitations, we provide important evidence to support the findings that ACE I/D polymorphism may be not associated with susceptibility to SCZ. However, we could not completely exclude the possibility that other SNPs within the ACE gene modify development of SCZ. Future researches with larger cohorts should be warranted.
1170
Letter to the Editor / Psychiatry Research 220 (2014) 1169–1171
Fig. 1. Forest plot for the association between ACE I/D polymorphism and SCZ risk. Each study is shown according to the point estimate of OR with 95% CI. A: Allelic model (D vs. I); B: Homozygotes model (DD vs. II); C: Dominant model (DDþ ID vs. II); D: Recessive model (DD vs. IDþ II).
Letter to the Editor / Psychiatry Research 220 (2014) 1169–1171
Acknowledgments This work was supported by the National Natural Science Foundation of China (No.81301147). References Arinami, T., Li, L., Mitsushio, H., Itokawa, M., Hamaguchi, H., Toru, M., 1996. An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and affective disorders. Biological Psychiatry 40, 1122–1127. Baskan, N.M., Basaran, A., Yenilmez, C., Kurt, H., Ozdemir, F., Gunes, H.V., Degirmenci, I., 2010. Investigation of association between Angiotensin-converting enzyme gene insertion/deletion polymorphism frequency in Turkish patients with schizophrenia. Genetic Testing and Molecular Biomarkers 14, 753–757. Crescenti, A., Gasso, P., Mas, S., Abellana, R., Deulofeu, R., Parellada, E., Bernardo, M., Lafuente, A., 2009. Insertion/deletion polymorphism of the angiotensinconverting enzyme gene is associated with schizophrenia in a Spanish population. Psychiatry Research e165, 175–180. Hui, L., Wu, J.Q., Zhang, X., Lv, J., Du, W.L., Kou, C.G., Yu, Y.Q., Lv, M.H., Chen da, C., Zhang, X.Y., 2014. Association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and first-episode patients with schizophrenia in a Chinese Han population. Human Psychopharmacology 29, 274–279. Illi, A., Kampman, O., Anttila, S., Roivas, M., Mattila, K.M., Lehtimaki, T., Leinonen, E., 2003. Interaction between angiotensin-converting enzyme and catechol-Omethyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. European Neuropsychopharmacology 13, 147–151. Kantojarvi, K., Onkamo, P., Vanhala, R., Alen, R., Hedman, M., Sajantila, A., Nieminen-von Wendt, T., Jarvela, I., 2010. Analysis of 9p24 and 11p12-13 regions in autism spectrum disorders: rs1340513 in the JMJD2C gene is associated with ASDs in Finnish sample. Psychiatric Genetics 20, 102–108. Kucukali, C.I., Aydin, M., Ozkok, E., Bilge, E., Zengin, A., Cakir, U., Kara, I., 2010. Angiotensin-converting enzyme polymorphism in schizophrenia, bipolar disorders, and their first-degree relatives. Psychiatric Genetics 20, 14–19. Meerabux, J., Iwayama, Y., Sakurai, T., Ohba, H., Toyota, T., Yamada, K., Nagata, R., Irukayama-Tomobe, Y., Shimizu, H., Yoshitsugu, K., Ohta, K., Yoshikawa, T., 2005. Association of an orexin 1 receptor 408Val variant with polydipsiahyponatremia in schizophrenic subjects. Biological Psychiatry 58, 401–407. Nadalin, S., Buretic-Tomljanovic, A., Rubesa, G., Jonovska, S., Tomljanovic, D., Ristic, S., 2012. Angiotensin-converting enzyme gene insertion/deletion polymorphism is not associated with schizophrenia in a Croatian population. Psychiatric Genetics 22, 267–268. Ouyang, W.C., Wang, Y.C., Hong, C.J., Cheng, C.Y., Tsai, S.J., 2001. Association study of angiotensin-converting enzyme gene polymorphism with schizophrenia and polydipsia. Neuropsychobiology 44, 31–35.
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Rigat, B., Hubert, C., Alhenc-Gelas, F., Cambien, F., Corvol, P., Soubrier, F., 1990. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. Journal of Clinical Investigation 86, 1343–1346. Segman, R.H., Shapira, Y., Modai, I., Hamdan, A., Zislin, J., Heresco-Levy, U., Kanyas, K., Hirschmann, S., Karni, O., Finkel, B., Schlafman, M., Lerner, A., Shapira, B., Macciardi, F., Lerer, B., 2002. Angiotensin converting enzyme gene insertion/ deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia. American Journal of Medical Genetics 114, 310–314. Wang, K.S., Liu, X., Zhang, Q., Aragam, N., Pan, Y., 2011. Genome-wide association analysis of age at onset in schizophrenia in a European-American sample. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 156B, 671–680. Yuan, J., Jin, C., Qin, H.D., Wang, J., Sha, W., Wang, M., Zhang, Y., Zhang, F., Li, J., Yu, S., Qi, S., Shugart, Y.Y., 2013. Replication study confirms link between TSPAN18 mutation and schizophrenia in Han Chinese. PLoS One 8, e58785.
Guofu Zhang Wuxi Mental Health Center Affiliated to Nanjing Medical University, Wuxi 214151, Jiangsu Province, China Mental Health Institute of The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China Feng Zhang, Jianzhong Zhu, Fuquan Zhang, Jianmin Yuan, Chunhui Jin n Wuxi Mental Health Center Affiliated to Nanjing Medical University, Wuxi 214151, Jiangsu Province, China E-mail address: [email protected] (C. Jin) Zhimin Xue nn Mental Health Institute of The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China E-mail address: [email protected] 16 August 2014 Available online 16 September 2014
n nn
Corresponding author. Tel.: þ 86 510 83250132; fax: þ 86 510 83012201. Corresponding author. Tel.: þ 86 731 85294015; fax: þ86 731 85533525.